title: Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer.
abstract: BACKGROUND
  The sigma-2 receptor has been validated as a biomarker for proliferating tumours. Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria into the cytosol, leading to apoptosis. In this study, we investigated a sigma-2 ligand as a tumour-targeting drug delivery agent for treating ovarian cancer.
  
  
  METHODS
  A sigma-2 ligand, SW 43, was conjugated with a Smac mimetic compound (SMC), SW IV-52s, to form SW III-123. The delivery function of the sigma-2 moiety and cell killing mechanisms of SW III-123 were examined in human ovarian cancer cell lines.
  
  
  RESULTS
  SW III-123 internalisation into ovarian cancer cells was mediated by sigma-2 receptors. SW III-123, but not SW IV-52s or SW 43, exhibited potent cytotoxicity in human ovarian cancer cell lines SKOV-3, CaOV-3 and BG-1 after 24-h treatment, suggesting that the sigma-2 ligand successfully delivered SMC into ovarian cancer cells. SW III-123 induced rapid degradation of inhibitor of apoptosis proteins (cIAP1 and cIAP2), accumulation of NF-κB-inducing kinase (NIK) and phosphorylation of NF-κB p65, suggesting that SW III-123 activated both canonical and noncanonical NF-κB pathways in SKOV-3 cells. SW III-123 cleaved caspase-8, -9 and -3. Tumour necrosis factor alpha (TNFα) antibody markedly blocked SW III-123-induced cell death and caspase-3 activity in SKOV-3 cells, indicating that SW III-123 activated both intrinsic and extrinsic apoptotic pathways and induced TNFα-dependent cell death in SKOV-3 cells.
  
  
  CONCLUSIONS
  Sigma-2 ligands are a promising tumour-targeting drug delivery agent. Sigma-2-conjugated SMC exemplifies a novel class of therapeutic drugs for treating ovarian cancer.
authors.affiliation: Division of Radiological Sciences, Department of Radiology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zeng
authors.forename: S
authors.initials: S
authors.lastname: Vangveravong
authors.forename: J E
authors.initials: JE
authors.lastname: McDunn
authors.forename: W G
authors.initials: WG
authors.lastname: Hawkins
authors.forename: R H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D017480:Receptors, sigma; D014409:Tumor Necrosis Factor-alpha; C106107:sigma-2 receptor; D020169:Caspases